Several lines of evidence support the idea that the FHIT is a potential tumor suppressor gene, playing an etiological role in "in vivo" tumorigenesis: it is disrupted by the t(3;8) chromosomal translocation observed in a family with multiple cases of renal cell carcinoma (RCC); it encompasses the FRA3B aphidicolin common fragile site; it spans the 3p14.2 region that is a target of homozygous deletions in various human cancer-derived cell lines (from head and neck, stomach, colon, cervical, breast, kidney and other tumors); it contains an integration site for oncogenic HPV 16 viruses; replacement of Fhit expression in four different cancer derived cell lines suppressed their tumorigenicity in nude mice. We hypothesize that alterations of the FHIT gene are involved in the process of carcinogenesis of sporadic primary clear RCC and occur also as constitutional abnormality in families with an aggregation of RCC and other chromosome 3p-related tumors (e.g. lung, head and neck carcinomas). Analysis of somatic abnormalities of the FHIT gene in a series of primary clear RCCs of different morphological grade and clinical stage and constitutional changes in families with at least three close relatives affected by kidney and/or lung and/or head and neck cancers is the aim of this proposal. Because unusual complexity of DNA leasions at the FHIT locus its integrity will be studied at DNA, RNA, and protein level; in every sample analysis of Fhit protein expression will be done by immunohistochemistry. Analyses of the FHIT gene changes in primary clear RCC will verify directly if this gene is important in kidney tumorigenesis and will contribute a basis for further investigations on various aspects of genotype-phenotype correlations in kidney tumors. Analyses of the FHIT gene constitutional abnormalities can be crucial in diagnosing individuals and families with high inherited risk for renal cancers and other 3p-related malignancies.